Project Summary Aging is associated with cognitive decline in otherwise healthy older adults, thus the forecasted increase in age of the population will place an even larger number of people at risk for impaired cognition and dementia-related diseases, such as Alzheimer's disease. This highlights the need for therapeutic approaches that maintain functionality of the aging brain. The hippocampus is a brain region that is highly vulnerable to the effects of aging, with reduced synapse formation and synaptic plasticity leading to impaired learning and memory-related processes. While historically the aged brain was presumed unable to combat the challenges of aging, accumulating research demonstrates that the aged brain, and particularly the hippocampus region, is capable of rejuvenation, offering promise to counter age-related cognitive decline. Indeed, rejuvenating systemic interventions, such as heterochronic parabiosis (in which the circulatory systems of young and old mice are joined), have been demonstrated by our lab and others to improve synaptic plasticity and cognition in aged mice. Thus, the search for circulating pro-youthful factors has garnered much attention. Our lab has shown the plasma component of blood to be particularly effective at reversing neuronal and hippocampal-dependent cognitive impairments in aged mice. Subsequent work investigating the role of the circulatory system in rejuvenating the aged brain has focused on the identification of soluble protein factors within young blood plasma capable of rejuvenating neuronal and cognitive function in aged mice. Interestingly, using a centrifugation approach, we have identified platelets remaining in young blood plasma. However, the rejuvenating potential of young platelets, and their released factors, has yet to be explored. Preliminary data suggest that systemic administration of platelets isolated from young plasma enhances associative memory in aged mice. Furthermore, using a proteomic mass spectrometry approach, we have identified Platelet Factor-4 (PF4) as a potential platelet-derived pro-youthful circulating factor. Therefore, the goal of this proposal is to investigate the role of young platelets, and their released circulating factors, in mediating rejuvenation of the aged hippocampus. I will test this theory using three Specific Aims: 1: Determine the potential of young platelets to reverse age-related cognitive dysfunction in the aged hippocampus. 2: Evaluate the role of young platelets in promoting neuronal rejuvenation in the aged hippocampus. 3: Investigate the role of platelet-derived circulating factors in rejuvenating the aged hippocampus. Ultimately, these studies will have significant translational potential, identifying potential novel therapeutic targets to restore functions underlying cognitive impairments in the elderly, and reducing susceptibility to dementia-related neurodegenerative diseases, such as Alzheimer's disease.